Single-cell RNA sequencing reveals dysregulated cellular programmes in the inflamed epithelium of Crohn's disease patients.
Krzak, M.; Alegbe, T.; Taylor, D. L.; Ghouraba, M. H.; Strickland, M.; Satti, R.; Thompson, T.; Arestang, K.; Przybilla, M. J.; Ramirez-Navarro, L.; Harris, B. T.; Cheam, K. A. X.; Noell, G.; Leonard, S.; Petrova, V.; Jones-Bell, C.; James, K. R.; Wana, N.; Hu, M. X.; Skelton, J.; Ostermayer, J.; Gu, Y.; Dawson, C.; Corridoni, D.; Cotobal, C.; Parkes, M.; Iyer, V.; Jones, G.-R.; McIntyre, R. E.; Raine, T.; Anderson, C. A.
Show abstract
Crohns disease (CD) is a chronic inflammatory bowel disease exhibiting substantial heterogeneity in clinical presentation and response to therapy. To explore its molecular basis, we developed IBDverse, the largest single-cell RNA sequencing (scRNA-seq) dataset of terminal ileal biopsies, profiling over 1.1 million cells from 111 CD patients and 232 healthy controls. This resource integrates discovery and replication cohorts for robust identification of CD-associated cell types, genes, and pathways. We uncovered epithelial changes marked by interferon-driven MHC-I upregulation, persisting in progenitors after macroscopic inflammation resolution. ITGA4+ macrophages were identified as key inflammatory drivers, showing enriched JAK/STAT signaling and cytokine expression (IL-6, IL-12, IL-23). Heritability analysis linked inflammatory monocytes and macrophages to CD susceptibility, implicating resident and recruited immune cells in pathogenesis. These findings establish a comprehensive cellular and molecular framework for CD, offering new insights into disease mechanisms and therapeutic opportunities.
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